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Every CLL patient is unique, and researchers are constantly refining their understanding of how CLL works and what treatment options are best for individual patients. In this program, learn what factors you should consider when making your treatment decisions as Dr. Ian Flinn of the Johns Hopkins Oncology Center and Dr. Chadi Nabhan of Lutheran General Hospital Cancer Care Center in Park Ridge, Ill. share their insights about new approaches to CLL therapy.

This HealthTalk program is supported through an unrestricted educational grant from Berlex.

Announcer:

Welcome to this HealthTalk program, CLL Updates: More Treatments, More Choices. Researchers are continually refining their understanding of chronic lymphocytic leukemia and the goals of CLL therapy. In a moment, you'll hear the latest on CLL treatment from two prominent medical experts. Before we begin, we remind you that the opinions expressed on this program are solely the views of our guests. They are not necessarily the views of HealthTalk, our sponsor or any outside organization. As always, please consult your own physician for the medical advice most appropriate for you. Support for this program is provided to HealthTalk through an unrestricted educational grant from Berlex. We thank them for their commitment to patient education. Now, here's your host, HealthTalk's Andrew Schorr.

Andrew Schorr:

Hello. I'm Andrew Schorr. As an nine-year CLL survivor myself, I have a keen interest in our topic tonight, and we're fortunate to have with us two experts in the field of hematology and oncology who have dedicated their lives to helping CLL patients live longer, healthier lives. They're here to update us on new research findings and their practical implications for those of us who are living with CLL, whether you are newly diagnosed or have had previous treatment.

I'll start by introducing Dr. Ian Flinn. Dr. Flinn is an associate professor of oncology at the Johns Hopkins University in Baltimore. He is director of the lymphoma program there, as well as assistant director for clinical research at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.

Also with us is Dr. Chadi Nabhan, a specialist in hematology and medical oncology at the Lutheran General Hospital Cancer Care Center and Rush North Shore Medical Center, both in the Chicago area. Dr. Nabhan also has an academic appointment as a clinical assistant professor of medicine at Northwestern University's Feinberg School of Medicine in Chicago.

As both of our guests know, the days of the one-size-fits-all approach to CLL seem to be over. New tests are enabling specialists such as Dr. Flinn and Dr. Nabhan to profile CLL patients, if you will, and then recommend treatment based on an individual's specific situation. Treatments have become more targeted and refined in the past few years, and even our understanding of what constitutes remission from CLL is changing. Dr. Flinn, set the stage for us please by briefly outlining the changes in assessment and treatment of CLL.

Dr. Ian Flinn:

I think you said it very nicely. It's clear that one size does not fit all and that all patients aren't equal and that we'll hopefully soon close the era where everyone's going to get the same therapy. We have a better idea now that there are certain differences in genetic factors of the patient's leukemia that tend to respond to different therapies and have different prognoses. It won't be appropriate in the near future to treat everyone the same way.

At the same time, some of the ways we're thinking about our traditional approaches to staging are changing a little bit too. These new prognostic factors and new understanding of CLL trumped our traditional staging methods. The goals of therapy are changing as well. It's clear that if patients get into a very good remission, meaning beyond our ability to detect CLL, these patients often do better. The goals are changing, and how far we want to treat someone into remission is changing.

Finally, we have new therapies that are called targeted therapies. Mostly, we're talking about the monoclonal antibodies, but there are other therapies that are coming along that target the disease in different ways.

Andrew:

[That's] exciting for those of us living with the disease, knowing that these therapies are getting better, and your knowledge and understanding of the disease is increasing at lightening speed. We thank you for helping lead the way on that with your own research.

Dr. Nabhan, based on what Dr. Flinn said, when you're seeing a newly diagnosed patient in 2005, what prognostic, or predictive, tests are now a standard part of your workup? What do these tests tell you about the treatments that might be most appropriate for that patient?

Dr. Chadi Nabhan:

When we have a patient that has CLL, it's important to recognize prognostic factors for that particular patient. Based on these factors, you may define new therapies.

Now, in the office when patients are seen, it's important not to lose the original, clinical prognosticators we have used for many years. We have new things going on, but we still have to look at the complete blood count - the (CBC - and the absolute lymphocyte count, and what we call the lymphocyte doubling time (LDT). Although this is not as sophisticated as some of the tests we'll be discussing, I still think they actually do provide us with helpful clinical information.

I do check the CBC. I do check the LDH [a blood test that measures the amount of lactate dehydrogenase] and the beta-2 microglobulin (B2M), which are two simple serum tests to help me assess the bulk of the disease. Certainly, kidney and liver function tests are important because they may preclude certain therapies and carry some prognostic significance.

Once I establish these factors, then I move to the more sophisticated studies. I think many of these studies are available across the board in small community hospitals as well as larger university settings. We use FISH [fluorescence in situ hybridization] to detect these chromosomal abnormalities. We specifically look for four translocations [transfer of a part of a chromosome to a new location on the same chromosome or another chromosome]. Basically, we look for specific abnormalities that are detected in CLL that may have prognostic implications. We look at the CD38 status. We do that using [testing techniques called] immunophenotyping and flow cytometry. Together, these tests plus the usual clinical factors, not to mention the physical exam, help in deciding how I'm going to approach the patient.

Andrew:

Dr. Flinn, in addition to the tests that Dr. Nabhan mentioned, there are others that are not yet widely used or may currently be in clinical trials. What are some of these tests, and how might doctors use this information to determine the course of therapy?

Dr. Flinn:

I use all or most of those tests that were just outlined. Basic parameters are still very important in making decisions about when to start therapy.

There are two big ones that have gotten a lot of play. The two tests that are starting to help physicians and patients make treatment decisions are known as mutational status, as well as ZAP-70. Unfortunately, these tests are still very difficult to get clinically.

ZAP-70 is a protein that's usually seen in T cells [a type of lymphocyte] but can show up abnormally in leukemia cells and has been shown in a number of research studies to have very important prognostic information. The problem with the ZAP-70 test is that it is very difficult to do. There are a whole bunch of different methodologies, but there are problems with almost all of these methodologies. I'm not sure that I believe the test when patients come to me and they've had it done elsewhere, by a different commercial lab. I read it, but I'm not sure it factors very heavily into my treatment decisions because it usually hasn't been validated against very large studies.

The other one [test] is the mutational status of the immunoglobulin gene, the variable region of that gene [IgVh gene mutation status]. In this case, having a mutated gene is a better prognostic factor than being unmutated. Again, this is a very powerful tool. It's very difficult to get although we're going to start sending it out to a commercial lab that now has it up and going. Previously, it's been so expensive that no one was willing to do it because they couldn't get reimbursed for it. But I think that's changing, and hopefully that will be available on a more widespread basis. If it were available, I think it would be very important. It correlates well, but not completely and not entirely, with CD38 expression.

The FISH - looking at the chromosomal abnormalities, the cytogenetics - is probably one of the most widely available and most important tests right now. The other tests that are out there that are only at the main research labs at this time include angiogenesis markers and P53 abnormalities other than the one that is picked up by FISH. When they are done in a research lab, you really shouldn't be making patient decisions with that.

Andrew:

It's always interesting to me that if you're mutated, it's better than if you're unmutated. You'd think if there's a mutation that would be a wrong change but maybe not in CLL.

Dr. Flinn:

It's the only time I know that being mutated sounds good.

Andrew:

With all this new information, are there still situations in which these various tests don't really give you definitive answers about a person's treatment options?

Dr. Flinn:

There certainly are [these situations]. There are cases where some of these tests come out in opposite directions, and you have a hard time knowing exactly what to make of all that. The other thing is these tests, like many tests for prognostic factors, are probabilities, and any given patient may or may not behave like the statistical curve. These studies are good for predicting outcomes for a thousand people, and, in general, they are pretty good at picking outcomes for any individual, but there are always cases where that's not true, where someone has a poor prognostic factor and does very well, and where someone who looks on paper like they should be doing great, unfortunately, has a very poor course. You have to take some of these things with a little bit of a grain of salt.

Now, that said, there's a lot of work going on trying to integrate all of these prognostic factors. There's been work in the United States and in Europe looking at integrating FISH, C38 results, mutational status and so forth, into an algorithm that can try to predict the likelihood of needing therapy soon based on these tests. It's still a work in progress, but one of the many things that have come home are that the FISH cytogenetics, such as having abnormalities of 17p and probably 11q, are some of the most powerful prognostic factors. If someone has one of those, then the poor prognosis of that probably outweighs any good prognostic factor that they might have.

Andrew:

Dr. Nabhan, in your practice, have these new prognostic tests changed the standard of care for people with early-stage CLL?

Dr. Nabhan:

That's really the million dollar question. How do we actually integrate this flood of information that we get into better therapies for patients? The short answer is no. We do get a lot of this information. However, for [people with] early-stage CLL who are completely asymptomatic and have adequate marrow function, adequate red cells, platelets, and are not on a clinical trial that is exploring that same question, I still think that watchful waiting remains the standard of care, with frequent follow-up.

If I have the prognostic factors that predict that my patient may have a high-risk profile - the 17p or the 11q [deletion] - I certainly would do more frequent follow-ups on this patient. I would advocate having the patient participate in a clinical trial that would be addressing that question.

On the other hand, in intermediate and later stage disease such as stage III or IV, usually these patients require therapy regardless of the prognostic factors, just based on the clinical presentation. The prognostic factors may assist in choosing the right treatment for these patients. Sometimes you can make the decision clinically regardless of the prognostic factors. The challenge is early-stage CLL patients who have no symptoms but have some risk factors based on this prognostic marker. What can we do best for these patients? Outside of a clinical trial, unfortunately, I still believe the standard of care is watchful waiting. But five years from now, we may be having the same conversation, and my answer will be completely different.

Andrew:

Dr. Flinn, let's talk more about some of the newer treatments for CLL. Monoclonal antibodies such as Campath [alemtuzumab] and Rituxan [rituximab] are certainly in the forefront today, and the buzzwords we're hearing are targeted therapy and personalized therapy. Help us understand what these treatments are and how they might change outcomes for people with CLL, whether they are used for initial treatment or as a follow-up approach.

Dr. Flinn:

It's important to understand, if we talk about monoclonal antibodies first, what really is a monoclonal antibody? It's very different from chemotherapy. The best way to explain a monoclonal antibody is that, [say] it's flu season and you get an influenza shot. Your body is developing an immune response against influenza that's going to protect you against that virus. Part of that is a protein, an antibody, that recognizes the virus as foreign. Through some fairly neat recombinant techniques [biotechnology] these days, one can produce in a laboratory an antibody that's specific for any target you really want.

For patients with CLL, a variety of antibodies have been developed over the years. The ones that are commercially available are the drugs Rituxan or Campath. These antibodies target two different proteins on the surface of CLL [cells]. In the case of Rituxan, it's CD20, which is an antigen that's on all these cells. It's not just for CLL but also for patients with B-cell lymphomas. Campath targets another antigen called CD52. CD52 is on basically all lymphocytes - not just B cells but T cells, macrophages and monocytes. If you're talking about targeted therapy, or selective therapy, you can have a more or less targeted treatment. In the case of Rituxan, it's targeting only B cells whereas Campath is targeting basically all lymphocytes, so it's a little bit less targeted.

Other targeted treatments that are in clinical trials are forms of immunotherapy such as vaccine approaches, where one is trying to specifically target the leukemia cells and have one's own immune system attack. These therapies are different than general chemotherapy. If you get a chemotherapeutic drug, the whole idea is that the CLL cells are going to be more sensitive than the normal bone marrow cells such as red cells and platelets or neutrophils. As time goes on, that becomes less and less true. And in some agents it's not true at all, and, unfortunately, you're getting as much damage to normal tissue as you are to the CLL cells.

The targeted therapies are very exciting because they have much less of a side-effect profile.

Andrew:

Are monoclonal antibodies now being used to prevent the progression of CLL?

Dr. Flinn:

Yes, they are [being used], most commonly with Rituxan, probably because it has a little bit better up-front side-effect profile. The concept is that people might use Rituxan when they are diagnosed even though they don't have the normal indications for treatment. They are treated on a regular schedule approach, maybe once every three months, maybe once every six months, to prevent patients becoming symptomatic. I don't think that that's standard of care at all. It's not something I do in my practice, and I definitely wouldn't do it outside of a clinical trial. I think it's an exciting idea and approach, but we have insufficient data to know whether that's a good idea or a bad idea in the long run. It might be a great idea in the sense that patients might go for many years without ever requiring therapy. It might be a bad idea in the sense that perhaps using Rituxan in that fashion, early on, then it would be less effective when one really needed it. That question is not answered at this time.

Andrew:

Dr. Nabhan, how critical is the initial treatment decision for someone with CLL? Are there some early treatments that might take you out of the running for other treatments later on?

Dr. Nabhan:

I think the initial treatment decision is very critical in CLL and all other malignancies because, as you said, the initial choice could affect what other choices you may have in the future. Every treatment that we give could have potential side effects and toxicities. These toxicities may actually prevent us from using other therapeutic interventions later on. Higher doses of alkylating agents [chemotherapy], for example, could cause a lot of bone marrow suppression. Then if this patient may need transplant in the future or stem cell collection with his own cells, this may be a problem. Some use of drugs that could cause cardiac side effects could prevent further conditioning regimens for transplants.

The short answer is that treatment decisions should be individualized based on the patient profile, based on co-morbid conditions [medical conditions other than the cancer] and the side effects of the treatment. It's not unreasonable that at the time the patient's requiring therapy to ask one, two or even three people just to see what alternatives there are, what other oncologists would use, what clinical trials are available. I don't think any of us, as oncologists, would be upset if our patients go and seek another opinion. It's certainly something reasonable, especially at the juncture where therapy is to begin.

Andrew:

Dr. Nabhan, what are the indications that treatment for CLL should begin, in your opinion?

Dr. Nabhan:

This is really a moving target now, but we are using the NCI [National Cancer Institute] criteria for starting therapy. This usually constitutes patients who would have symptoms related to their disease such as fevers, night sweats, unintentional weight loss, patients who have bulky adenopathy [enlargement of the lymph nodes] that could be causing significant organ damage or even cosmetic problems; certainly, patients who have bone marrow suppression with low red cells and low platelets related to the malignant lymphocytes infiltrating the bone marrow and preventing the production of red cells and platelets. Certainly, if patients have massive splenomegaly [enlarged spleen] or organomegaly, in general, these are the current NCI working group criteria for starting therapy. I do believe in the next few years, these prognostic factors and molecular markers will be integrated into this. I wouldn't be surprised if, in several years, for patients who have the 17p deletion or the 11q [deletion] because we know that they may do poorly, our threshold to start therapy may be a little bit lower than for other patients.

Andrew:

What are the current standards for first-line treatment now?

Dr. Nabhan:

You may get several answers depending on who you ask and their geographic location, and that's why other opinions may be important. For years, alkylating agents such as chlorambucil [Leukeran], chlorambucil with prednisone, or other alkylating agents have been used, such as a regimen called CVP (cyclophosphamide, vincristine and prednisone). I do reserve the alkylating agents to an older individual who has many other co-morbid conditions, and [in whom] the disease is not causing a lot of symptoms.

But these are falling out of favor as opposed to another class of drugs called purine analogs. The most famous drug that we have used in CLL is fludarabine [Fludara]. Fludarabine has been shown to have a higher response rate than the alkylating agents. This could probably translate into faster improvement in symptoms. For years, we've used single agent fludarabine, and recently there has been the interest in what we call chemo-immunotherapy, which is combining the fludarabine with monoclonal antibodies such as Rituxan. This regimen, fludarabine and Rituxan together, is gaining popularity partly because we know from other diseases, types of lymphomas, that combining chemotherapy with monoclonal antibodies is producing success. We are seeing similar results in outcome in CLL.

I think chemo-immunotherapy is very appropriate as initial therapy. Whether adding anything to a regimen of FR (fludarabine and rituximab) such as cyclophosphamide, which makes the regimen now FCR, would add much, I'm not clear. I think both of them [FR and FCR] are appropriate initial therapy, but be careful because it may effect future therapy. Personally, in my practice, I utilize fludarabine with Rituxan as initial therapy. I don't use the cyclophosphamide with that.

Andrew:

I know there is a national study going on to determine whether adding the C (cyclophosphamide) is helpful or not. What are the side effects and long-term risks associated with these treatments?

Dr. Nabhan:

The major side effects, in my opinion, are infectious complications. I think [with] any purine analog-based therapy, we have to be very careful. Patients need to be on prophylactic antibiotics to prevent bacterial, fungal and viral infections. Those are pretty much the standards that all oncologists usually implement at the time of starting therapy. Sometimes prolonged bone marrow suppression, or cytopenia [low blood cell counts], is observed with fludarabine or with purine analogs. If patients are being offered other therapies that include an anthracycline, whether it's Novantrone [mitoxantrone] or Adriamycin [doxorubicin], in another regimen, I think cardiac side effects as a long-term possibility are there.

Andrew:

Dr. Flinn, let's talk about new research and ongoing clinical trials for CLL. Was there any research news about CLL at the recent annual meeting of the American Society of Clinical Oncology (ASCO)?

Dr. Flinn:

There certainly has been [research news] at both ASCO and ASH (American Society of Hematology) in the last year. It depends on of what stage a patient is in the natural history of the disease. Did they have prior therapy or not? Some of the trials that are going on now are looking at adding a variety of monoclonal antibodies to treatment regimens, such as a new anti-CD23 antibody that's being developed. Does that add anything to the FCR regimen?

There is another important question in clinical trials. Does Campath used as an adjuvant after chemotherapy or chemo-immunotherapy clean up the last remaining (leukemic) cells once a patient is in a good partial remission? Trying to get to minimal residual disease (MRD), does that help anything? There are a variety of other antibodies that are also much earlier in development, antibodies trying to alter the survival signals that come sometimes from one's own immune system that keeps CLL cells alive. These are antibodies directed against blocking CD40 ligand or a whole other family of survival proteins called BLISS or BATH.

There are some other monoclonal antibodies that are just entering into clinical trials based on a very different premise than ones we've seen in the past, where the whole idea was just to pick a target that happened to be on that CLL cell and hopefully cause the cell to die. Here, we're looking at trying to overcome some of the ones known as host survival signals. So it's a very exciting time for drug development for patients with CLL.

Andrew:

For people who have been previously treated, Dr. Flinn, help us understand if they're either not responding to therapy or are going to need therapy to help them better manage their illness than traditional chemotherapy, what's available now?

Dr. Flinn:

The big question is, how long were you in remission? If, unfortunately, you just received a fludarabine-based regimen and didn't stay in remission very long or didn't respond at all, then there are some new antibody approaches that are being developed and some very novel approaches. The other thing to think long and hard about, no matter how young or old you are, would be a mini-bone marrow transplant, which are really coming of age and increasingly proving their efficacy for patients with CLL and low-grade lymphoma. That's something that someone should seek out - an opinion at a transplant center - if they are not responding to conventional therapies or the remission duration was very short.

Andrew:

Was there anything you wanted to mention further about clinical trials before we move on to questions?

Dr. Flinn:

There are other exciting agents that are out there too. I didn't mention a drug that was previously tested in the late '90s, flavopiridol, that unfortunately showed lackluster results, and it was dropped. But John Byrd and Mike Grever at Ohio State really kept with it. They couldn't understand why the results in the laboratory were not what they were seeing in patients and did a lot of hard work and found out that there was really a problem with the way the drug was being delivered. The drug levels really weren't high enough that patients' CLL cells would be sensitive to it.

Through a bit of serendipity, an investigator in Belgium or France was conducting a trial at the same time, in the late '90s. He accidentally gave the entire dose of flavopiridol to a patient that was supposed to be a continuous infusion over a day, in an hour. Remarkably, that patient had lysis, destruction of all his CLL cells, and a very nice response. That clinical data along with laboratory data that the doctors that I mentioned had been working on led to a revitalization of flavopiridol. There are studies going on at Ohio State where they have had remarkable responses in patients that hadn't responded to anything before. So I think that drug is going to make a comeback and hopefully will be very important for patients with CLL in the future.

Andrew:

Let's take a question from Kingston, Tennessee. Rex writes, "Tell me about changed blood counts after chemo treatment for CLL. I've heard it referred to as my 'new normal.' What does that mean?"

Dr. Nabhan:

Obviously, you would assume that anybody with CLL, on the blood count, you'll have malignant lymphocytes. Let's say the majority of the white blood cells will be lymphocytes as opposed to another type called neutrophils. Probably the red cells, or the hemoglobin, will be slightly low, and the platelets will be below 100,000, or abnormal. Giving the chemotherapy or whatever choice of treatment for CLL should reverse the percentage of these white blood cell counts. It should kill the lymphocytes, so hopefully our patient will have a higher percentage of the neutrophils and an absolute lymphocyte count usually less than 5,000 in the peripheral blood. Hopefully, the hemoglobin is back to normal, 11 or 12 and above, and the platelets are above 100,000. In general, if patients achieve this, this would be the new normal, which is achieving some sort of remission or response.

Dr. Flinn:

I've had patients that are a little disturbed when their white count is lower than what should be normal. This is probably because they have had very effective therapy that's gotten rid of all the lymphocytes in their blood. As a normal consequence of most of the treatment we use, we're unfortunately getting rid of normal lymphocytes as well as malignant lymphocytes. It's not abnormal after treatment with chemotherapy or antibodies to have a total white blood cell count that's lower than what the patient might think they are supposed to have.

Andrew:

Right. But [this is] not necessarily dangerous?

Dr. Flinn:

Correct.

Andrew:

I was in exactly that situation for a while and [had] lower platelets, too, but they came back over time. Gerry from Washington, D.C., writes, "A recent article by Dr. David Frank of Harvard [University] and Dr. Jack Arbuser of Emory [University] talked about the use of honokiol for the treatment of CLL. He said apparently they have found that honokiol, which is a derivative of magnolia tree bark, can overcome the resistance to apoptosis, or allowing cancer cells to die. Is this a possible breakthrough in the search for a cure for CLL?"

Dr. Flinn:

I'm not familiar with that paper. I do know some of David Frank's other studies looking at natural substances and removing the blockade to apoptosis, or death of cells. I can't speak to that specific paper. But the field of work of looking at trying to remove blocked apoptosis is an important one in CLL that many people are looking at, not only with natural products but with novel compounds.

What we're talking about is something that will help trigger death in these cancer cells, which often hang around and gum things up otherwise and don't die. Is that correct?

Dr. Flinn:

Right.

Andrew:

Larry from San Diego, your question is about when to start treatment, is that right?

Larry:

That's right and whether age is an issue in whether you do tests and when you start.

Dr. Nabhan:

I do think in the majority of cancer therapy, it's not really the chronological age that we care about in choosing therapy, it's more about how well a patient looks and what we call performance status. Probably age by itself does not alter what tests I will do.

In terms of when to start therapy, I really think we still go by the NCI working group criteria to start treatment, which are really mainly clinical. We look at the symptoms that the patient may be having. If there are constitutional symptoms - those will be fever, unintentional weight loss, night sweats, chills, a decline in performance tests related to the disease - that may be an indication to start therapy. Other indications [are] these bulky or massive lymph nodes that may be bothersome or may be compressing on certain organs of the body that may cause problems later on. Other possibilities include so much CLL that it has actually infiltrated the bone marrow, causing low red cells, or anemia, and low platelets, or thrombocytopenia. As we discussed, there's a lot of interest in changing these criteria and trying to understand whether treating someone early on if they have the poor prognostic markers will be beneficial. There are active clinical trials that are addressing these issues.

Andrew:

John in Ames, Iowa, writes, "I'm a 32-year-old male who was diagnosed with CLL two years ago. I'm doing very well. No treatment is needed as of now. My oncologist routinely does FISH tests. The last FISH test decreased from 57 percent to 48 percent cells having trisomy 12. This is the first time it went down. Does this happen often? I take this as a good sign."

Dr. Flinn, [do you have] a comment on this decrease in this indication in FISH?

Dr. Flinn:

It's unusual for someone to lose a cytogenetic abnormality without therapy. I suspect it's just a statistical aberration [intrinsic variability of the test]. The bigger question is whether we should be doing serial FISH testing or not. That's an unanswered question as well. It appears that maybe there is utility in this, in the sense that we are picking up new abnormalities. But I've so far resisted most of this and don't do them that often. I usually would do them initially, and then I might do them at the time I was contemplating a treatment decision. I usually don't do them once a year unless there has been some clinical parameter or reason that I think I ought to do it.

Andrew:

I have one follow-up question for you. You mentioned the term earlier, minimal residual disease. You've treated someone, and you're trying to see how well that treatment has done. There are tests coming out for that. How do you feel about that - to measure how you're doing and how long to keep treating?

Dr. Flinn:

They are probably going to be very important to us in the future. It's a chicken-and-egg phenomenon. We're not exactly sure that extra cycles of chemotherapy will result in a better outcome for patients. We do know that patients get to very minimal residual disease, and what we mean is that, in the classic staging techniques or response criteria, someone would do a bone marrow [biopsy] and look for CLL that might still be left in the patient's bone marrow.

The problem with that is it's based on morphological tests, basically, a pathologist or a hematologist looking under a microscope at the bone marrow and trying to differentiate a normal lymphocyte from a CLL cell. They often look very similar. It's normal to have up to 30 percent lymphocytes in your bone marrow. Someone can have 30 percent lymphocytes, which might be all CLL cells, and still be considered in complete remission, where other, more sophisticated, tests such as flow cytometry would show that you still had a lot of CLL in the marrow.

Many investigators have looked at trying to use these techniques, such as flow cytometry or PCR [polymerase chain reaction], or other techniques to try to determine whether someone was in a true complete remission, meaning that they, to the best of their ability with the most sophisticated techniques, couldn't find any CLL anymore. At any rate, I think that many of the clinical trials are using that as an end point now instead of the NCI's normal definition of a complete remission, which is just based on morphology.

Andrew:

Alice, from Bridgeton, New Jersey, has a question about post-chemo options.

Alice:

Is Campath [alemtuzumab] alone an appropriate treatment for someone who has been treated with standard chemotherapy, or would you add another agent to that? The last time he had standard chemotherapy was in 1999. He went on maintenance Rituxan [rituximab] for two-and-a-half years, and now it's not working for him. Should he go on Campath alone or in combination with another drug?

Dr. Nabhan:

I think it's debatable, but the bottom line, I think, is that he did well for about five years after chemotherapy. At this stage, when the disease now is starting to behave aggressively again or just showing manifestation of activity, the options could be reattempting the same chemotherapy that the patient received because it had a durable remission that lasted for five years. Provided that the patient tolerated that particular therapy well, I think there is enough evidence that they may have additional responses that are durable.

If chemotherapy is not an option, I think Campath is a very reasonable single agent option. The single agent trial that was published several years back showed a response rate in the range of 33 percent, and many patients had a response that lasted a year or two.

Depending on the age of the patient, I would advocate checking the prognostic factors that we have here. I'd like to know if he has 17p [deletion] or the p53 mutation. I wouldn't be opposed, if he does not have the 17p or the p53, to trying purine analogs. If he does have the p53 or the 17p, I would favor using Campath based on information that was released over the past 12 months.

Andrew:

Dr. Flinn, did you have anything you wanted to add?

Dr. Flinn:

The other important thing is just because the disease is now detectable that doesn't necessarily mean that a patient needs therapy again. The same indications for initial therapy apply to relapse as well. So the disease is back, someone can see it, it's detectable, I would still watch and wait until they had all those signs and symptoms that led to the decision to start the therapy to begin with.

Andrew:

Dennis in Sausalito wrote, "Have either of you tried Campath as a maintenance program after a complete remission has been reached, for example, once every month or two or in doses of 15 milligrams rather than 30 milligrams?" Dr. Flinn, [do you have] any comment on that?

Dr. Flinn:

I've never used it as a maintenance approach. In some patients, that might be appropriate, where they have known abnormalities of p53 or 17p and there weren't other treatment options available. You'd have to be concerned about the immunosuppression and the risk of not only bacterial infections but fungal infections and other opportunistic infections. I wouldn't advocate that on a routine basis, that's for sure.

Andrew:

Helen from Dallas has a question about when to have testing.

Helen:

In your standard workup, you did not speak to any bone marrow testing. I was wondering when you would do this type of testing.

Dr. Nabhan:

That is an important question. I don't think you need to have a bone marrow biopsy or aspiration to diagnose the disease. You could have the diagnosis by examining the peripheral blood [CBC] and doing an adequate physical exam and so forth. However, I do think that the bone marrow biopsy and aspiration provide very important information. I tend to do a bone marrow biopsy and aspirate in standard practice, outside of a clinical trial, at the time I decide to initiate therapy. If I've been doing watchful waiting for several years and now there are the indications for me to start therapy, doing a bone marrow [test] is very reasonable. In order for me to believe that my patient has attained a remission, I need to repeat a bone marrow [test] after chemotherapy and see the pattern of bone marrow change. Also, at that time, the pattern of infiltration of the bone marrow may have some prognostic implications. And, obviously, if I'm looking for minimal residual disease, which we're not discussing here, I usually do a bone marrow [test].

Dr. Flinn:

I agree completely. I don't do it anymore at diagnosis. I don't think it adds anything. But having a baseline before you give someone a treatment, if problems occur, if someone develops autoimmune problems, it's helpful to know what the marrow looked like beforehand to make that diagnosis in the middle of treatment.

Andrew:

Rick from Wyoming says, "Could you take a moment to mention improvements in side-effect management?" I had terrible nausea five years ago when I had treatment. I know there's been a lot of progress there and with other biotech products for infection risk and also for fatigue."

Dr. Nabhan:

I do think that we can still do better. No matter how well we have done over the past several years, I still think we can do better and hopefully we will.

I always tell my patients that there are side effects they are afraid of more, and there are side effects I am afraid of more. The side effects that patients usually fear include nausea, vomiting, constipation or diarrhea. We have good drugs [for nausea prevention], the 5HT3 inhibitors, Zofran [ondansetron], Kytril [granisetron], Anzemet [dolasetron]. We have other drugs that inhibit substance P release from the brain that hopefully will prevent delayed nausea and vomiting. We utilize all of these drugs together to minimize the toxicity.

The other important supportive measures include growth factors, which could be the Neupogen [filgrastim] and the longer-acting pegfilgrastim, which is Neulasta [pegfilgrastim]. Those are two drugs that help in maintaining the neutrophil count above a dangerous level to minimize the side effects and toxicity of infections. Certainly, Procrit or Epogen [epoetin alfa] prevent anemia and chemotherapy-induced anemia.

The side effects that I fear more than anything else are infections related to the treatment. That's why I think we need to be on top of using prophylactic antibiotics and try to maintain the white blood cell count, neutrophil count specifically, in a level that is safe enough for patients to minimize their toxicity.

Andrew:

I would put a pitch in for those of you going through treatment to speak up if you're feeling some of these side effects because there is no reason to suffer. Your doctor will be looking for infection, but you want to stay on your treatment plan so those drugs to fight the cancer can be used most effectively to knock that CLL way back and, of course, hope for a cure.

Steve in Palatine, Illinois, said, "I was diagnosed with CLL in 1995. I've had a variety of treatments, Fludarabine, FCR, maintenance Rituxan and a stem-cell transplant. I was told at M. D. Anderson that they have some new experimental drugs and to give serious thought to another mini-allotransplant with a harsher chemo preparation. Is there anything else worth considering before a transplant?" He also says, "Does it matter where you have a transplant?"

Dr. Nabhan:

The indications for any therapy for CLL are always the same whether the patient is at relapse or starting of therapy or at diagnosis. If he's already had the transplant and he is in remission, I would advocate doing nothing. If there is evidence of disease, depending on his age and his performance status, after all of these therapies, I think clinical trials are the way to go, or considering another mini-transplant if he is in good shape. Where the transplant is done is very critical. I think doing a transplant in a place where there is familiarity with the side effects, there's a high volume of transplant, is very important. Many centers are very comfortable with the autologous transplant. But [with] the allotransplant, it's important to be in a large center. I would like to know a little bit more about his case before I would recommend the harsher regimen and transplant. It's hard to answer that appropriately.

Andrew:

This is really a discussion for you and your doctor. We encourage you to get a second opinion, maybe even a third one because these are very critical decisions.

Dr. Flinn, what advice do you have for CLL patients who want to ensure they're getting the best treatment, especially if they not able to go to a major cancer center like yours at Johns Hopkins?

Dr. Flinn:

Programs such as this are important. The most important thing is to be knowledgeable and be an active participant in the decisions about your therapy. That can be done locally if you can find someone who is knowledgeable in your community and has a particular interest in CLL, or if you have an oncologist/hematologist who is willing to seek out advice from others. That is often a very good sign - they are willing to listen and talk to their colleagues and learn more.

Andrew:

You're encouraged by where we are in CLL now?

Dr. Flinn:

It continues to be a very exciting time in CLL research in terms of a variety of very different strategies all aimed at eventually curing this disease that are now making their way from the laboratory into the clinic. I am very encouraged.

Andrew:

It's great to hear that from you since you're on the forefront of all this. Dr. Nabhan, you are a community hematologist/oncologist. What specific steps can people living with CLL take to ensure they are getting the most progressive and thorough care and treatment wherever they live?

Dr. Nabhan:

Seeking information is very important. I do always caution my patients about verifying the source, where they get the information. There is wrong information out there as well as good information, so it's important to verify the source and be very careful who to listen to.

I really advocate second opinions. It never insults an oncologist who has a patient go and seek another opinion because, ultimately, this is for their sake.

Lastly, I think it's really an exciting time for CLL because we know more about the biology of the disease, we know more about the pathophysiology of the disease.

Andrew:

Dr. Flinn and Dr. Nabhan, thank you so much for being with us. As a patient, I know it's been very informative and reassuring that we're making real progress in this disease. I know our audience joins me in wishing you both well as you help us move toward a cure.

Our guests have been Dr. Ian Flinn of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore and Dr. Chadi Nabhan from Lutheran General Hospital Cancer Care Center and Rush North Shore Medical Center in Chicago.

From our studio in Seattle and all of us at HealthTalk, we wish you and your family the best of health.

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